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  • On the other hand the single stranded RNA flavivirus hepatit

    2022-01-21

    On the other hand, the single-stranded RNA flavivirus hepatitis C virus (HCV), causes type C hepatitis, which often leads to liver cirrhosis, hepatic failure and hepatocellular carcinoma. Its genome of about 9.6kb encodes the structural proteins C, E1, E2, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. Since the NS3-NS4A protease plays a critical role in HCV viral replication, this dimeric serine protease has been viewed as a promising target for screening anti-HCV drugs.3, 4 Currently approved anti-HIV drugs, including highly active antiretroviral therapy (HAART) with a combination of HIV PR inhibitors and reverse transcriptase inhibitors, have remarkably decreased the mortality of AIDS patients and improved the quality of life of those infected with HIV.5, 6 However, because HIV easily mutates and rapidly develops drug resistance, it remains a leading cause of death worldwide, resulting in more deaths than any other infectious disease due to inadequate access to HIV prevention and treatment. As with hepatitis C, clinical options are currently limited, and the only available drugs are subcutaneous pegylated interferon (pegIFN-α) alone or in combination with oral ribavirin (Rbv), the therapeutic effectiveness of which is only 50% for HCV infected patients.8, 9, 10 In light of the potential offered by chemoprevention, novel effective and safe agents are urgently required. We reported that some natural products and their derivatives have anti-HIV-1 PR activity. Of these, some triterpenes, such as ganoderic Marimastat sale B and ganoderiol B,N-(3β-hydroxylolean-12-en-28-oyl)-6-aminohexanoic acid, hemiesters of ursolic acid, 3-oxotirucalla-7,24-dien-21-oic acid, 16β-hydroxy-2,3-seco-lup-20(29)-en-2,3-dioic acid and colossolactone V, are potent inhibitors of HIV-1 PR. We also reported that embelin, 5-O-methylembelin as well as some indole derivatives inhibited HCV PR. Several studies over the past decade have demonstrated that pentacyclic triterpenes especially oleanolic acid (OA), ursolic acid (UA), betulinic acid (BA) and glycyrrhetic acid (GA) as well as their derivatives inhibited HIV.21, 22 However, the abilities of tetracyclic triterpenes, especially dammarane-type triterpene derivatives to inhibit HIV and HCV PRs have not been reported. Ginseng roots contain abundant ginsenosides mainly consisting of dammarane-type triterpenes as the aglycones, such as protopanaxadiol and protopanaxatriol. However, these aglycones convert to panaxadiol (PD) and panaxatriol (PT), respectively under strong acid conditions. PD and PT have the same A ring moiety, but PT possesses one more hydroxyl group in B ring, that is, PT is 6α-hydroxy-PD. Panaxadiol has two hydroxyl groups at C-3 and C-12 in the A and C rings, respectively, whereas PT has three hydroxyl groups at C-3, C-6 and C-12 in the A, B and C rings, respectively. These functional groups provide footholds to convert A—seco and acylated derivatives. Here, we describe the preparation of dammarane-type triterpene derivatives by modifying the hydroxyl groups in the A, B and C rings, and their abilities to inhibit HIV-1 and HCV PRs as well as the human aspartyl and serine proteases renin and trypsin, respectively.25, 26
    Results and discussion
    Conclusion Starting from the artificial aglycones, (20R)-PD and (20R)-PT derived from an acid hydrolysate of a ginseng extract, we prepared a series of dammarane type derivatives bearing a 2,3-seco-2,3-dioic acid (3a and 3b) moiety or 2,2-dimethylsuccinyl functional group(s) at C-3 (5a–5c) or C-6 (5d) or at both positions (5e and 5f). Of seventeen tested compounds, eight were powerful inhibitors of HIV PR with IC50 values of 2.7–11.9μM. Among these, the mono-2,2-dimethylsuccinyl compounds 5a and 5d were the most active with an IC50 of 2.7μM. On the other hand, only compounds 3b and 5e were powerful inhibitors of HCV PR, (IC50 9.1 and 1.8μM, respectively), and compound 5a was moderately inhibitory. The structure–activity relationships (SARs) of these compounds remarkably differed between the two viral proteases; most of the 2,2-dimethylsuccinyl derivatives (5a–5e) potently inhibited HIV PR, whereas only the di-2,2-dimethylsuccinyl (5e) and 12-oxo-2,3-seco-2,3-dioic acid (3b) derivatives potently inhibited HCV PR. Methylation of the carboxyl group in A-nor dammarane type compounds significantly decreased the inhibitory activities against both proteases. Thus, our study demonstrated that structural modification of dammarane-type triterpenes, especially (20R)-PD and (20R)-PT, leads to derivatives with powerful inhibitory activity against either HIV or HCV PR. Compounds with high inhibitory activity on HIV or HCV PR were inactive against renin and trypsin, suggesting low physiological toxicity. Based on these findings, we believe that dammarane-type triterpene derivatives bearing a 2,3-seco-2,3-dioic acid moiety or 2,2-dimethylsuccinyl group(s) will provide valuable information for the development of new anti HIV and HCV agents.